Typhoid fever (Enteric fever)

Typhoid fever in children for medical students and doctors

1. - Dr. Lokanadha Reddy M V Consultant Paediatrician Sreenika children’s clinic Bangalore ENTERIC FEVER/TYPHOID FEVER

2. Salmonellosis - Why? Common and widely distributed Global major public health problem Affecting millions Food borne disease Significant mortality

3. ETIOLOGY Salmonella enterica serovars (Gm -ve) Typhi ( S.Typhi ) - Most common Paratyphi - very similar but less severe A B (Schotmulleri) C (Hirschfeldii) Disease ratio 10:1 (Typhi : Paratyphi)

4. EPIDEMIOLOGY 26.9 Million typhoid cases/year worldwide (80%) 1% mortality MC in Asia 5.4 Million paratyphoid cases/year (20%) 12 Million DALY More in children < 5 years, of incidence, complications and hospitalisation

5. Gram-Negative Facultative Rods Family - Enterobacteriaceae, like E.Coli Habitat - Intestinal tract of warm and cold blooded animals Causes 2 diseases Enteric fever - Bloodstream infection AGE - Food-borne infection MICROBIOLOGY

6. Gm -ve Rods Flagellated Motile Produce H2S on thiosulphate

7. Enterobactiriaceae Eschericia Coli Shigella Citrobacter Salmonella enterica Enterica (>99.5%) Salamae Arizonae Diarizonae Indica Bongori Houtenae Family Species Subspecies S.Typhi S.Paratyphi A,B,C Serovars

8. Somatic (O) /
Cell wall antigens Surface (Envelope) antigens Flagellar (H) antigens Heat stable
Alcohol resistant May mask O antigens Heat labile Used for serological studies Vi antigen occurs in only 3 servers Used for serological studies Typhi, Paratyphi C and Dublin Antigenic structure

9. Cultures: XLD agar Blood agar HE agar

10. Exotoxins: Enterotoxin, Cytotoxin have role in diarrhoeal symptoms Genetics: Plasmids in salmonella code for antibiotic resistance Most specific gene products - Vi (virulence) polysaccharide capsule, seen in 90% of S.Typhi and has protective effect against bactericidal action of serum of infected patients Antibiotic susceptibility: Resistance to Ampicillin, streptomycin, chloramphenicol, sulphonamides. Colistin resistance is not yet observed. DOC till 1972 was chloramphenicol. In 1972 chloramphenicol-resistant strains emerged.

11. EPIDEMIOLOGY Resistant to Ampicillin, chloramphenicol & Cotrimoxazole Increased resistance to Nalidixic acid (Quinolone) and Fluoroquinolones Mode of transmission: Ingestion of foods or water contaminated with human feces, seafoods contaminated with sewage water Risk factors : Antacids, PPI, H2 blockers - reduce infective dose

12. PATHOGENESIS Infective dose 10 5 -10 9 Gut mucosa - terminal ileum Street food contaminated water M cells, Enterocytes Paracellular route Attaches to microvilli & stays in payers patches Mesenteric lymph nodes Blood (1 o Bacteremia) Asymptomatic, B/C -ve Reticuloendothelial system - replicates in macrophages Liver, spleen,GB,BM Blood (2 o Bacteremia) Clinical symptoms End of Inc. Period (4-14 days) Down regulates host inflammatory response Re-exp. of PP via Bile Pro-inflam. ck (IL-6,IL-1B,TNF-a) —> Fever Enterotoxin, cytotoxin —> Diarrhoea Host Risk factors : HIV, H.pylori

13. PATHOLOGICAL CHANGES INTESTINE: Hyperplasia of payers patches —> subsequent necrosis and sloughing of overlying epithelium —> Ulcers —>heal without scarring or stricture Occasionally ulcer may penetrate muscularis and serosa causing intestinal perforation MLN, LIVER, SPLEEN: Hyperaemic with focal necrosis BM: Mononuclear response with focal necrosis

14. CLINICAL FEATURES IP : 7-14 days (3-30 days) Mild illness : Low-grade fever, malaise, slight dry cough Severe illness : Abdominal discomfort and complications Factors influencing severity : Duration of illness before initiating correct therapy, choice of antibiotics, age, previous exposure or vaccine, virulence of strain, infective dose, host immune factors More dramatic presentation & complications in < 5 years Infancy : Diarrhoea, toxicity, DIC, more fatality Rare in children : Relative bradycardia, neurologic manifestations, GI bleeding (common in adults)

15. CLINICAL FEATURES

16. CLINICAL FEATURES Fever : Prolonged High grade (up to 105’F) with chills and rigors, Initially low-grade at onset and rises gradually, classic step ladder pattern is rare. Child is not active during inter-febrile period. Unlike viral fever which peaks at the onset of fever. Rash : 25% have macular or maculopapular rash (rose spots) - 7th-10th day (2nd week), in crops of 10-15 on lower chest and abdomen, lasting 2-3 days Hepatosplenomegaly : seen in 35% cases and 15% cases respectively Malaise, dull headache, anorexia, nausea, abdominal discomfort, coated tongue Bronchitis like picture in early days with rhonchi and crepitations

17. CLINICAL FEATURES Diarrhoea: With fever is a common presentation, classical pea soup diarrhoea seen in early days. Later constipation ensues with mild abdominal distension, diffuse tenderness and paralytic ileus. Early constipation may be due to obstruction of hypertrophied payer’s patches. Atypical presentation in malaria endemic areas Multidrug-resistant Typhoid : more severe, more toxicity, complications and mortality Usually resolves in 2-4 weeks Drug-resistant Paratyphoid also can be severe

18. COMPLICATIONS LIVER: Altered liver function is seen in many but clinically significant jaundice, hepatitis and cholecystitis are rare and a/w adverse outcomes INTESTINE: Hemorrhage (<1%) and perforation (0.5-1%) are rare in children. Seen in 2nd-3rd week Perforation -> markedly increased abdominal pain(RLQ), tenderness, vomiting, peritonitis features like Tachycardia, hypotension, rigidity, guarding. Rising TLC, left shift and free air in AXR are seen. TOXIC MYOCARDITIS: Rare, a/w arrhythmias, Sinoatrial block, cariogenic shock

19. COMPLICATIONS CNS: uncommon in children. Delirium, psychosis, raised ICT, Acute cerebellar ataxia, chorea, deafness, GBS. Mortality is more(50%) but recovery is complete with no sequelae. Called severe or complicated enteric fever. OTHERS: Fatal BM necrosis, DIC, HUS, pyelonephritis, nephrotic syndrome, meningitis, endocarditis, parotitis, orchitis, suppurative lymphadenitis CARRIER: Chronic carrier rates lower in children

20. DIAGNOSIS BLOOD CULTURE: Gold standard, positive in 40-60% cases in 1st week. Sensitivity 90% in 1st week to 40% in 4th week. Bile-broth media/BACTEC. Sufficient blood 10ml in adults/5ml in children in 1:5 ratio of blood: media to be collected STOOL CULTURE: Positive after 1st week. Occasionally positive in incubation period URINE CULTURE : Positive after 1st week BONE MARROW CULTURE: More sensitive but invasive, may help in PUO evaluation

21. DIAGNOSIS CBC: TLC: Frequently low in relation to fever and toxicity like 4000-5000 cells/uL, but a wide range is seen. In younger children leukocytosis is common up to 20,000-25,000 cells/uL Eosinopenia, Neutrophilic predominance can be there PLT : Usually normal. Thrombocytopenia + Anemia is a marker of severe illness and a/w DIC CRP : High, vs Low in dengue/viral fevers LFT : may be deranged but significant hepatic dysfunction/jaundice is rare. AST/ALT may rise to 2-3 times

22. DIAGNOSIS WIDAL TEST : Measures antibodies against O and H antigens. Becomes positive after 5 days of fever Lacks sensitivity and specificity in endemic areas Many false-positive and false-negatives occur Diagnosis of typhoid on widal alone is prone to error O titres - 1:160 -> acute enteric fever (appears early) H titres - 1: 160 -> Past infection/immunised(positive in recovery) Rising titres to four-fold are significant but its time-consuming process Positive results may represent previous infection Widal does not access Vi Antigens, so its not false positive for newer vaccines but may be for classical TA vaccine.

23. DIAGNOSIS TYPHIDOT: A dot ELISA kit that detects IgM and IgG antibodies to OMP-outer membrane protein Becomes positive in 2-3 days Sensitivity - 100% and specificity - 80% Limitation: Only Qualitative not quantitative like widal test IgM IgG Interpretation + + Acute enteric fever + - Early acute infection - + Past infection

24. DIAGNOSIS Newer tests using MABs directly detect S.Typhi specific antigens in serum or Vi Ag in urine. These are not proved efficient. Nested PCR using H1- d primers is promising and provides rapid diagnosis. “BASU” - Blood culture, Agglutination (widal) test, Stool culture and Urine culture in 1st, 2nd, 3rd and 4th weeks.

25. DIFFERENTIAL DIAGNOSIS ACUTE GASTRO-ENTERITIS BRONCHITIS, BRONCHO-PNEUMONIA MALARIA SEPSIS TUBERCULOSIS, BRUCELLOSIS, LEPTOSPITOSIS VIRAL FEVERS, DENGUE, ACUTE HEPATITIS, INFECTIOUS MONONUCLEOSUS

26. TREATMENT Early diagnosis and appropriate treatment Vast majority can be managed at home with oral antibiotics and close follow-up for complications or failure of response to Rx Hospitalisation and IV antibiotics : Persistent vomiting, severe diarrhoea, abdominal distension Adequate Rest, Hydration and correction of fluid and electrolyte imbalance.

27. TREATMENT ISOLATION : should be nursed with precautions ANTIPYRETICS : Paracetamol 10-15mg/kg PO every 4-6 Hours. Ibuprofen can be used. Salicylates are contraindicated - shock. DIET : Soft, easily digestible diet except in abdominal distension or ileus ANTIBIOTICS : Critical to minimise complications STEROIDS: Dexa 3mg/kg ->1mg/kg Q6H x 48 hrs only in cases of severely ill with shock, (CNS signs) obtundation, stupor or coma. May mask abdominal signs.

28. TREATMENT CEFTRIAXONE : DOC for MDR typhoid as it is common Start 75-100 mg/kg/day OD/BD x 5-7 days Once afebrile, change to oral Cefixime x 10 days Superior to Cefotaxime because of its biliary excretion (kills bacteria in GB)

29. TREATMENT CEFIXIME : 20 mg/kg/day in two doses orally x 10-14 days for mild cases Can be used as follow up Rx for IV Ceftriaxone As a rule 1st/2nd gen. cephalosporins and aminoglycosides are not useful in treatment

30. TREATMENT CHLORAMPHENICOL : 50 mg/kg/day orally x 14 days in areas without resistant bacteria IV is given only if oral intake is not possible as 75mg/kg/day SE: Bone marrow suppression rarely. Undetectable reticulocytes gives the clue. “Gray baby syndrome”. Afebrile within 7 days of Rx If no response then unlikely to respond to Ampicillin, Amoxicillin, Cotrimoxazole Used apart from Aztreonam/Cotrimoxazole, in patients with penicillin or ceftriaxone allergy.

31. TREATMENT CIPROFLOXACIN : DOC for Adults and Children >12 years < 12 years can be given if ceftriaxone fails or in life-threatening cases Dosage: IV 20 mg/kg/day Q8-12H x 7-10 days Relatively safe in children If culture shows sensitivity to be downgraded to cipro because of lower relapse rates AZITHROMYCIN : 20 mg/kg/day (double dose) x 5 days

32. PRACTICAL TIPS As a general rule treatment (Ceftraixone) is until 5-7 days after defervescence For any Rx response is slow and takes 3-7 days Do not give laxatives or enema for constipation -can cause perforation Add Metronidazole and Aminoglycoside if perforation or peritonitis is suspected Osteomyelitis or Meningitis - Rx for 4-6 weeks

33. PRACTICAL TIPS If eosinophils appear which were absent earlier, indicates recovery Recovery signs : Subjective improvement, less toxic, improved appetite, general feeling better, improved feel of abdomen - soft and not distended, increasing interval between fever spikes, fever responding better and faster to antipyretics, lower fever spikes than earlier. If two antibiotics fail consider MDR typhoid. Stop the antibiotic and observe for 2-3 days if child is not toxic and ill. Repeat physical examination, CBC, CXR may help in difficult cases

34. PROGNOSIS Depends on age, early diagnosis and appropriate Rx, general health, nutrition salmonella serotype and complications RELAPSE: Despite App. Rx 5-15% may have relapse after initial clinical response. Milder illness. More with cephalosporins than with Fluoroquinolones/Azithromycin Chronic Carriers : who excrete S.Typhi > 3 mo. <2% in children and increases with age. Rx : Amoxicillin (100 mg/kg/day) with probenecid (30 mg/ kg/day) or cotrimoxazole (10 mg/kg/day) for 6-12 weeks is recommended. If the strain is nalidixic acid sensitive, quinolones for 28 days is better A chronic urinary carrier is seen in schistosomiasis

35. REFERENCES Nelson’s Textbook of pediatrics - 20th Edition OP Ghai Textbook of pediatrics - 8th Edition Santosh kumar manual of pediatric practice - 4th Edition Amdekar Lessons from grand rounds 2 Todar’s textbook of bacteriology - online edition